Nitric oxide, via activation of guanylyl cyclase, suppresses alpha2-adrenoceptor-mediated 5-hydroxytryptamine release from neuroendocrine epithelial cells of rabbit tracheae.
Isolated tracheae of newborn rabbits were incubated in vitro and the outflow of 5-hydroxytryptamine (5-HT) was determined by HPLC with electrochemical detection. Evidence has previously been provided that this 5-HT outflow derives from neuroendocrine epithelial (NEE) cells of the airway mucosa. Phenylephrine, at a maximally effective concentration of 10 microM, caused a transient increase in 5-HT outflow by about 250%, an effect mediated by alpha2B-adrenoceptors, as previously shown. The phenylephrine-induced 5-HT release remained unchanged in calcium-free medium, but was reduced by 75% when the tracheae were incubated in calcium-free medium which contained 0.5 mM EDTA, a treatment known to lower also intracellular calcium. The NO donor SNAP (S-nitroso-N-acetyl-penicillinamine, 10 microM) almost completely inhibited phenylephrine-induced 5-HT release. The inhibitory effect of SNAP was prevented by ODQ, (1H-[1, 2, 4]oxadiazolo[4, 3-a]quinoxalin-1-one), an inhibitor of soluble guanylyl cyclase. In contrast, 5-HT release induced by depolarizing concentrations of potassium (45 mM), which was reduced by 96% in calcium-free medium, was not affected by SNAP. In conclusion, NO, via activation of soluble guanylyl cyclase, inhibits 5-HT release from NEE cells in a stimulus-dependent manner. Alpha2-adrenoceptor-mediated 5-HT release, which appears to be triggered by liberation of calcium from intracellular stores, is suppressed by NO, whereas high potassium-evoked 5-HT release which is triggered by calcium influx through voltage regulated channels, is not affected.
Freitag
A
A
Institute of Pharmacology and Toxicology, University of Bonn, Germany.
Wessler
I
I
Racké
K
K
D000818:Animals; D000831:Animals, Newborn; D004789:Enzyme Activation; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D011817:Rabbits; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism*; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism
D018341:Receptors, Adrenergic, alpha-2; D010656:Phenylephrine; D009569:Nitric Oxide; D012701:Serotonin; D006162:Guanylate Cyclase